Vitamin D is critical in many physiologic and pathophysiologic processes including inflammatory status, immune function, and cardiovascular health. Vitamin D deficiency is widespread among HIV-infected adults and children. This is particularly alarming since there is a higher risk than the general population for complications like osteoporosis, non-AIDS-defining malignancies, and cardiovascular disease (CVD) - all diseases associated with vitamin D deficiency. It is not known how much vitamin D deficiency heightens the risk of complications like CVD, affects immune function and disease progression, or interferes with optimal treatment in the HIV population. The impact of vitamin D deficiency in the HIV population may be compounded even further since the etiology of HIV-related complications like CVD is thought to be related in part to inflammation and detrimental endothelial effects associated with chronic HIV infection-similar proposed mechanisms as vitamin D deficiency. Data suggest that optimal vitamin D status may be protective against these HIV-related complications, and optimizing vitamin D status with oral supplementation in HIV-infected individuals may improve the risk of HIV-related complications by decreasing inflammation and/or improving endothelial dysfunction, and may improve immune function even in individuals on antiretroviral therapy. Developing suitable repletion strategies is crucial to maximizing health status, particularly in HIV-infected children and young adults, where an opportunity exists for disease prevention. However, the best method of vitamin D repletion is not known, and data suggest that some antiretroviral medications interfere with vitamin D metabolism. Thus, we hypothesize that (1) optimizing vitamin D status to the current Institute of Medicine's (IOM) suggested 25-hydroxyvitamin D (25(OH)D) concentration of e20 ng/mL improves CVD risk, inflammation, and CD4 cell counts in HIV-infected individuals, (2) increasing 25(OH)D concentrations to >30 ng/mL improves CVD risk and inflammation to a greater degree than increasing eto 20 ng/mL (the concentration some experts consider optimal for cardiovascular health), and (3) a high dose of oral vitamin D is necessary to achieve 25(OH)D concentrations >30 ng/mL. These hypotheses will be addressed by determining the longitudinal relationships between serum 25(OH)D concentrations, carotid intima-media thickness, pulse wave velocity, pro-inflammatory biomarkers, and CD4 cell counts in HIV-infected children and young adults in a double-blinded, randomized-controlled trial of three different vitamin D dosing regimens given over 24 months in HIV-infected children and young adults (ages 10-25 years) with vitamin D deficiency (25(OH)D <20 ng/mL). We will also evaluate the 25(OH)D concentrations from each arm after 6, 12, and 24 months of supplementation, in order to determine a dose-response relationship. These findings could have a sizable impact on health in this population, since vitamin D therapy is inexpensive and associated with few adverse side effects. The PI is an exceptional candidate who is a pediatric infectious diseases specialist with a proven research focus in the metabolic and cardiovascular complications of HIV. She is mentored by a committed, multidisciplinary team of senior investigators with extensive experience in both mentoring and in the research methodologies relevant to this proposal. Future training in all aspects of clinical research, cardiovascular disease risk assessment, and clinical nutrition is planned to facilitate the PI's development into a successful independent physician scientist. PUBLIC HEALTH RELEVANCE: In most studies, HIV-infected individuals have a higher prevalence of vitamin D deficiency compared to uninfected individuals. Vitamin D deficiency may contribute to some of the long-term complications of HIV infection, such as cardiovascular disease and increased inflammation. This proposal will advance our understanding of whether correction of vitamin D deficiency affects the risk of these HIV-related complications and/or improves CD4 cell counts.